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Ethics considered during the study
Study conduction according to Helsinki recommendations, study and consent-form approvals from the local institutional ethical board (P.T.REC/012/003553; Faculty of Physical Therapy; Cairo University), consenting DE participants, and explanation of withdrawal rights to patients were the main ethical considerations of this study.
PMC10692261
Subjects
hypertensive
OBESE, DRY EYE
The included elderly (≥ 65 years old) were randomly selected obese hypertensive patients with DE. The elderly who finished the assigned interventions were 60 patients (Fig. Dry eye interventional flow chart
PMC10692261
Randomization protocol
The ED elderly were randomly and equally assigned via a computer-generated random list to the one of intervention-based groups (experimental and control groups). To guarantee the random blinded assignment of DE patients to groups, a physiotherapy practitioner (who did not know the interventions) planned the random list. For 6 months, both DE groups received HIIAE 3 times weekly while the experimental group received an additional MD plan.
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Interventions
PMC10692261
High-intensity interval aerobic exercise
On an electronic bicycle, for an average of 30 min, every HIIAE was conducted. The exercise was initiated with an average 5-min warming-up phase (DE participant performed this phase at 60% of maximal heart rate, abbreviated as MHR). High-intensity interval aerobic bicycling (HIIAB) was allowed after the warm-up ended for 2 min (the 2-min HIIAB was performed at 90% of MHR and this was considered as one interval exercise phase). After the end of one interval exercise phase, the DE patient is allowed to rest in the form of an active moderate-intensity continuous bicycling phase (active rest phase) at 60% MHR for 1 min. The cycle of interval and active rest phases was repeated 7 times with an average time of 21 min. The exercise session ended with a cool-down phase which was similar to the criteria of warming up.The elderly’s heart rate was monitored during every HIAB session using a heart rate monitor that was worn at the elderly’s wrist during bicycling.
PMC10692261
Protocol of MD
The MD protocol of this study was based on the recommendations of Bedard et al. [As a result of the above-designed MD protocol, the meal plan consisted of around 50% carbohydrates (the main source for carbohydrates was legumes, vegetables, fruits, and whole-product grains), 35% fats (the main source for fats was healthy oils, nuts/seeds, and fish), and 15% proteins (the main source for proteins was nuts, egg, poultry, low-fat dairy products, legumes, and fish).Based on the total daily requirement and degree of DE-participant’s activity (2000 kcal/d for ♂ and 1600 kcal/d for ♀), a calorie restriction of about 15% from the daily Kilocalories was proposed.During the 6-month research period, weekly consultations with a nutritionist were used to give nutritional counseling. The weekly visit was a chance for the nutritionist to assess patients ' diet adherence. All DE participants were taught how to complete a 24-h recall dietary evaluation of consumed foods, which was examined at each face-to-face nutritional session with the nutritionist.
PMC10692261
Prerequisite assessment (cardiopulmonary exercise test)
fatigue
This test was conducted one time only (before the conduction of the first HIIAB session in both study DE groups on an ergometer cycle). In order to make the patients adapt to the test steps during the test’s beginning, unloaded cycling was maintained for 3 min. To incorporate the patients in warming up, the cycling was loaded by 40 Watt. After the termination of the warm-up that reached 3 min, the examiner started to increase the load on the patient to 20 Watts every 60 s. The aim of this incremental loading was to reach the DE patients to one of the two following notices: patients’ sensed fatigue or 90% of MHR. If one notice was achieved, cooling down was started with the same criteria of warming up. The test was finalized with the unloaded cycling (0 watts for 3 min) [
PMC10692261
Pre and post-assessments
PMC10692261
Blood pressure and anthropometry
Diastolic blood pressure (DBP), systolic blood pressure (SBP), weight, body mass index (BMI), and waist circumference (WC) were measured in all DE patients.
PMC10692261
DE scoring system (DESS)
blurred vision, fatigue, abnormal excessive blinking, gritty/sandy sensation, ocular itching/burning
To assess the symptoms related to DE, this questionnaire was used. DESS asked about the presence of 6 items: eye fatigue, ocular itching/burning, local redness, gritty/sandy sensation, blurred vision, and abnormal excessive blinking. Every item is represented with an answer of zero (absent), one (sometimes), two (frequent), and 3 (always found). The score of DESS ranged from zero (minimal score) to 18 (maximal severe score) [
PMC10692261
Ocular surface disability index (OSDI questionnaire)
dry eye, ocular impairment, ’ environmental-activated ocular symptoms
DRY EYE
It is a valid surOcular surface disability index (OSDI questionnaire)vey that rates the severity of DE patients’ environmental-activated ocular symptoms and complaints in the previous week. The survey consists of 12 items, each of which is evaluated on a scale of 0 to 4, with 0 being an indicator of none of the time and 4 being an indicator of all of the time. The OSDI questionnaire includes a total score as well as 3 subscale scores: vision-associated symptoms (5 items), ocular symptoms (4 items), and environmental triggers or stimuli (3 items). The overall score of the OSDI questionnaire is gained by dividing the total score of all answered questions by the number of answered questions and then multiplying the result by 25. Then, the result of this equation was assessed on a 0–100 scale with higher scores detecting the ocular impairment. A 0–12 score of OSDI is an indicator of a normal eye (absence of DE). An OSDI score ≥ 13 is a diagnosis of dry eye [
PMC10692261
Schirmer’s test
This test was done to assess the speed of tear production. After 2 min of using topical anesthetic eye drops (0.4% benoxinate hydrochloride; Benox; Eipico, made in Egypt), the test was initiated. The test was conducted by the placement of Whatman’s no. 41 filter paper strips (5-mm width × 35-mm length) in the inferior conjunctival fornix (the filter paper was placed at the junction of the lateral
PMC10692261
Tear film break-up time (TBUT) testing
CONJUNCTIVA, CORNEA
It was done to assess tear film stability (i.e., time needed for tears to be evaporated and diffused after natural blinking). Briefly, sodium fluorescein (1% eye drops; Minims Fluorescein sodium; Baush + Lomb, Kingston-upon-Thames, England) was dropped into the conjunctiva sac. The participants were ordered to blink 3–4 times and then look forward without any blinking. The tear film was examined under the slit-lamp biomicroscope light. The time between the last blink and the emergence of the first break in the tear film (i.e., formation of a dry spot on the cornea) was recorded using a timer [
PMC10692261
Oxford grading system
cornea damage
CONJUNCTIVA
In DE sufferers, the Oxford grading system (OGS) was created to determine the extent of epithelial surface damage of conjunctiva and cornea damage. To initiate OGS, instilling a 10-µl fluorescein sodium in the superior conjunctiva was required. The OGS method employs a chart comprised of a sequence of panels (figures) referenced from A to E in ascending degree of severity. Staining is shown by punctate dots in each figure. From panels A to E, the number of drawn dots within every panel increases [The pre-interventional selected criteria for DE diagnosis in our study participants were based on the presence of at least one reported DE symptom on DESS [
PMC10692261
Sample size calculation
The number of DE patients was calculated by the popular estimating sample size program; G*power. This calculation was postulated in a conducted pilot study by the manuscript’s authors on 10 DE patients. The result for this calculation marked the sample size = 54 DE patients considering Schirmer’s test was the primary outcome. The value of 0.68 was the resultant effect size which was estimated on the statistical program with type II error = 0.8 and type I error = 0.05. Then, the number increased by 10% due to the estimation of dropout. So the final needed DE elderly were 30 patients in every group.
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Statistical analysis
Shapiro-Wilk test was used for investigating the normality of age, blood pressure anthropometry variables (height, weight, BMI, and abdominal circumference), duration of DE symptoms, and DE variables (DESS, OSDI questionnaire, TBUT, and Schirmer’s test). All previously mentioned variables were normally distributed, so parametric tests were used for analysis.Because of the non-normal distribution, a non-parametric test was used for OGS analysis. An unpaired Two-way MANOVA was employed to illustrate the difference between time (pre and post) and treatments (DE groups). To measure the size of the difference between DE groups, a partial eta square (
PMC10692261
Discussion
obesity, tumor necrosis, inflammation, hypertensive, metabolic syndrome, weight loss, dryness
OBESITY, OBESE, TUMOR NECROSIS, INFLAMMATION, DYSFUNCTION, SYSTEMIC HYPERTENSION, INTERSTITIAL FIBROSIS, METABOLIC SYNDROME
This study proved that exercise (HIIAB) can significantly relieve DE symptoms. DE relief can be also maximized by the additional effect of MD in obese hypertensive elderly with DE. The mechanism that explains the effect of MD or exercises on DE is not fully sufficient in the literature.The popularity of MD in improving cardiovascular risk factors (including obesity) [The included olive oil, vegetables, poultry, nuts, cereal products, and sometimes meat are main sources of some essential fatty acids (EFAs) as omega-6 EFAs (O6EFAs). The included marine oil and fish are sources of other EFAs, omega-3 EFAs (O3EFAs) [It is supposed that the good choice to within-diet healthy foods maintains the ratio of O6EFAs: O3EFAs within 1:1. This ratio can maintain regular inflammatory and immune responses within the human body. Some unhealthy Western diets are low in O3EFAs, so the ratio become 17:1 [The high level of O6EFAs accelerates the production of pro-inflammatory mediators including PGE2 and LTB4. The low level of O3EFAs cannot block the formation of interleukins and tumor necrosis factor-alpha. A higher O3EFAs to O6EFAs ratio exerts an anti-inflammatory and immune-enhancing effect. The health advantages of dietary O3EFAs consumption have been documented for DE [As an alternative to oral supplementation, the integrative components of MD foods contain the needed O3EFAs and O6EFAs for the maintenance of healthy connective tissue [As it was previously proven in immortalized epithelial cells of the human meibomian gland, the regular administration of O3EFAs and O6EFAs can improve the quality and quantity of intracellular lipids that maintain tear production from the lacrimal gland [Virgin olive oil, as an MD component, contains a large oleic-acid (monounsaturated fatty acid) content. This fatty acid protects the organs’ tissue against oxidative damage. Also, hydroxytyrosol, as a phenolic compound present in virgin olive oil, has anti-oxidative, anti-inflammatory, and neuroprotective properties. These properties may exert their effects on the health of the cardiovascular system [Regarding exercise, the exercise-induced harmony between the sympathetic and parasympathetic nervous systems may be the cause of increased tear production. This regulated harmony can stimulate the within-eye epithelial sodium channels. This stimulation, in turn, can increase sodium reabsorption which plays a vital role in the maintenance of water and electrolytes found in produced tears [As it was evidence-based in the literature, exercise-induced reduction of adipose tissue improves the associated cascades of chronic low-grade systemic inflammation present in cardiovascular risk factors [Despite the low number of published studies, a recent study supported our results because its authors documented a decrease in tear production (assessed by Schirmer’s test) in systemic hypertension patients when matched with normal control subjects [The results of a relatively new published animal study supported our results. This animal study stated two facts. The first fact was the low rate of tear production in obese mice. The second one was the ability of exercise to increase this rate in addition to the suppression of reactive oxygen specimens (ROS) found in the lacrimal gland of this obese mouse [Another study conducted on rats in 2010 showed that CR is a new therapeutic tool that can be utilized to prevent age-associated dryness of the eye or lacrimal gland dysfunction. This animal study concluded that there is a positive role of a 6-month CR approach in the significant improvement of tear volume, tear protein, oxidative-stress-related destruction in the lacrimal gland, and preservation of lacrimal gland functions and structures (decreased interstitial fibrosis, preserved mitochondrial structure, and increased density of acinar unit of lacrimal gland) [The published studies assessing the effects of lifestyle changes on human DE are very low. Supporting our opinion, weight loss through 6-month lifestyle changes (MD alone or combined with 45-min walking/day) can cause a significant improvement of TBUT, OGS, DESS, Schirmer’s test, and OSDI questionnaire in DE participants with metabolic syndrome [Supporting the role of exercise in preventing DE, another study showed a significant increase in tear production and a decrease of tear cytokines after involving 43 without-DE healthy participants aged = 23.3 ± 3.6 years in one session of moderate intensity 0.5-h aerobic exercise on a treadmill [Also, another study reported an association between DE and sedentary behavior or lower level of energy expenditure in humans [Despite the observed improvement of subjective symptoms and the number of definite criteria diagnosing DE, the results of objective tests (staining score, TBUT, and Schirmer’s test) conducted by Kawashima et al. [
PMC10692261
Limitations
The authors of this paper did not track results beyond the only measurement they did after the end of the six months of treatment, and therefore it is required to examine this part in the future.Future studies are requested to examine DE’s response to MD versus other weight-loss diets, HIIAB versus moderate-intensity energy-expenditure exercises, and aerobic versus resistance exercises.
PMC10692261
Acknowledgements
DRY EYE
The authors acknowledged responsibility for the whole content of this dry eye manuscript.
PMC10692261
Author contribution
hypertensive
DRY EYE, OBESE
The authors of this dry eye research developed the idea of performing aerobic exercise and nutritional counseling in the obese hypertensive patients, collected raw data of dry eye parameters, and wrote the scientific background of the presented dry eye paper.
PMC10692261
Funding
Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB).
PMC10692261
Availability of data and material
DRY EYE
The data of this dry eye paper will be available on request.
PMC10692261
Declarations
PMC10692261
Ethics approval
dry-eye
Ethical/institutional approval (given Cairo-University local approval identifier P.T.REC/012/003553) was applied to this dry-eye study.
PMC10692261
Consent to participate
DRY EYE
All patients with dry eye were consented.
PMC10692261
Informed consent
DRY EYE
Elderly with dry eye were consented using the by-Cairo-university approved informed consent (P.T.REC/012/003553).
PMC10692261
Consent for publication
Not applicable.
PMC10692261
Competing interests
The authors declare competing interests.
PMC10692261
References
PMC10692261
Background
sexual dysfunction, disorder of the thyroid gland, Hypothyroidism
HYPOTHYROIDISM
Hypothyroidism is the most common clinical disorder of the thyroid gland which is associated with an increased prevalence of sexual dysfunction even if treated with medication.
PMC10204666
Objective
HYPOTHYROIDISM
The aim of this study was to determine the effect of cognitive-behavioral therapy (CBT) on sexual function in reproductive-aged women with hypothyroidism.
PMC10204666
Materials and methods
hypothyroidism
HYPOTHYROIDISM
This randomized clinical trial was performed on 66 reproductive-aged women with hypothyroidism referring to selected health centers in Izeh, Iran. Data collection tools included demographic information form and Female Sexual Function Index (FSFI). Eligible individuals were randomly assigned to case (n = 33) and control (n = 33) groups using block randomization with the block size of 4. In addition to standard hypothyroidism treatment, the case group received 8 sessions of cognitive-behavioral group therapy, while the control group received only standard treatment.
PMC10204666
Results
Before of treatment, there was no significant difference between the mean score of sexual function and its dimensions between the case and control groups (p < 0.05). However, immediately and 4 weeks after completion of treatment, the mean total score of sexual function and its dimensions in the case group increased significantly compared to the control group (p < 0.001).
PMC10204666
Conclusion
sexual dysfunction
HYPOTHYROIDISM
According to the results of this study, CBT can be effective in improving sexual dysfunction in reproductive-aged women with hypothyroidism. However, before recommending this therapy to women suffering from hypothyroidism, more detailed studies are needed to prove the effectiveness of this intervention, as an adjuvant treatment to the standard pharmacotherapy.
PMC10204666
Keywords
PMC10204666
Introduction
bradycardia, Sexual dysfunction, hoarseness, anxiety, dyspareunia, chronic diseases face similar challenges, chronic diseases, constipation, sexual disorders, weight gain, disorders of desire, sexual dysfunction, psychiatric, ’s behaviors, Nezamnia, in sexual desire, hypothyroidism
DISORDER, BROWN, DYSPAREUNIA, THYROID, DISEASE, CHRONIC ILLNESS, CHRONIC DISEASES, DISORDERS, SEXUAL PROBLEM, HYPOTHYROIDISM, HYPOTHYROIDISM
Thyroid is an active hormone gland that forms part of the hypothalamic-pituitary-thyroid axis [With a prevalence of 2 − 10% in different communities [In addition to physical problems such as weight gain, constipation, dry skin, bradycardia, hoarseness, slowed mental processing, and sexual disorders [This disease also increased prevalence of sexual dysfunction in both sexes (men and women). In women, hypothyroidism is associated with disorders of desire, arousal, satisfaction and orgasm, as well as dyspareunia (Although, the cause of the relationship between hypothyroidism and sexual dysfunction has not been clearly defined. However, some possible causes including changes in mood and circulating sex hormone levels through peripheral and central pathways, directly and indirectly, may be relevant in this context [Hypothyroidism can be the source of symptoms such as anxiety and stress in patients. Because the level of anxiety and stress in patients with hypothyroidism has been reported to be unfavorable, treatment of the associated mental disorders in these patients, in addition to alternative treatment with levothyroxine, seems necessary [Sexual dysfunction involves a disorder in sexual desire and psychosocial changes that affect the sexual response cycle and cause interpersonal stress and problems [Despite different etiologies, people with chronic diseases face similar challenges in managing their disease. These challenges include adjusting their lifestyle, dealing with emotions and psychological responses to chronic illness, coping with disease-related symptoms, and adherence to medication regimens and using a medication regimen. While there are many strategies for self-management or improving self-care activities and optimizing health while living with a chronic illness, CBT is a way that can bring good results for people with chronic physical illnesses. Lukkahatai et al. (2019) in a review study reported the role of CBT in the management of chronic diseases and its effect on controlling symptoms and improving the quality of patients’ life [Halford and Brown also introduced CBT as an adjunctive treatment for people with chronic physical illnesses. In this of patients, items such as psychiatric disorders associated with the illness, difficulty in adapting to the illness, difficulty in compliance with treatment, and problems with the patient’s behaviors will be well managed using cognitive-behavioral therapy [In the meantime, CBT is one of the ways to improve undesirable sexual function. Nezamnia et al. (2020) showed that compared to routine perinatal care counseling based on CBT improves sexual function and sexual self-efficacy of pregnant women [In cognitive therapy, therapists consider the process of cognitive processing to be more important than physiological factors and believe that the discovery of negative autosuggestion is helpful in the successful analysis of sexual problems [Despite the high prevalence of sexual dysfunction in patients with chronic diseases such as hypothyroidism and the importance of treating sexual dysfunction, doctors, health care providers and patients often ignore it [As far as we know, there is no previous study on this topic. Thus, the present study was conducted to determine the effect of CBT on sexual function in reproductive-aged women suffering from hypothyroidism.
PMC10204666
Materials and methods
PMC10204666
Study design and participants
hypothyroidism
HYPOTHYROIDISM
The present study was a randomized controlled clinical trial performed on 66 reproductive-aged women with hypothyroidism referring to selected health centers (Health Center No. 1, Comprehensive Medical Services Center No. 4) in Izeh, Iran. This research was approved by the Ethics Committee of Ahvaz Jundishapur University of Medical Sciences (Ref. ID: IR.AJUMS.REC.1398.387). This study was also registered in the Iranian registry for clinical trials (Ref. ID: IRCT20200706048030N1, 01/09/2020). The study started on August 18, 2020 and ended on October 19, 2021.
PMC10204666
Inclusion and exclusion criteria
hypothyroidism
HYPOTHYROIDISM
Inclusion criteria: women who were literate, aged between 18 and 45 years, and diagnosed with clinical hypothyroidism by an internal medicine specialist based on TSH levels were eligible to participate in this study. It should be noted that subclinical patients were not included in this study.Exclusion criteria: women with a history of receiving training based on cognitive-behavioral approach, and a history of known chronic and acute physical and mental illnesses or using psychotropic drugs prescribed by a physician or psychiatrist were excluded from the study.
PMC10204666
Sample size calculation
Based on a study by Atis et al. [
PMC10204666
Sampling
hypothyroidism
HYPOTHYROIDISM
Sampling started after receiving the code of ethics by the Ethics Committee of Jundishapur University of Medical Sciences in Ahvaz and registering the study in the Clinical Trials Center of Iran. The researcher attended in selected health centers in the Iranian city of Izeh. The women referred to these centers were selected through purposive sampling. The eligible women with diagnosis of clinical hypothyroidism based on laboratory tests were referred to an internal specialist for definitive diagnosis. Then participants were briefed on the objectives of the study, written consent was obtained from them, and they were assured that their information would remain confidential. Finally, 66 women aged 18 to 45 years diagnosed with clinical hypothyroidism and FSFI Score equal to or less than 26.5 who met the inclusion criteria were included in the study.
PMC10204666
Randomization
In this study, participants were randomly assigned into the case (n = 33) and control (n = 33) groups based on block randomization with the block size of 4 and allocation ratio of 1:1 using random sequence generation software.In order to conceal random allocation, sequentially numbered, sealed opaque envelopes were used. Thus, after performing a random sequence, a number of envelopes with aluminum wrappers (in order to obscure the contents of the envelopes) were prepared in proportion to the research sample size, and each of the random sequences created was recorded on a card. The cards were then placed in envelopes. In order to maintain a random sequence, the envelopes were numbered on their outer surface in the same way. Finally, the lids of the envelopes were glued and the envelopes were placed inside a box. At the time of registration of participants, according to the order of entry of eligible participants into the study, an envelope was opened and the participant was assigned to one group.Since the study could not be blinded due to the nature of the research, in order to reduce the possibility of bias, the type of intervention was assigned to the participants in the two study groups by a person who was involved in neither sampling nor data analysis. The calculation of the score of the female sexual function questionnaire of the patients was evaluated by a person who was not aware of the study process.
PMC10204666
Intervention
thyroid disorders, sexual dysfunction
THYROID DISORDERS, SESSION, DISEASE, THYROID DISORDER
In addition to standard pharmacotherapy, participants in the case group (n = 33) received CBT in 8 sessions, while the control group received only standard pharmacotherapy. After coordination with eligible individuals, treatment sessions were held regularly on a specific day, once a week, for the case group, each sessions lasting from 1.5 to 2 h. CBT was performed by one of the researchers (AS) who had received the necessary training and received the relevant certificate. All treatments were performed under the supervision of an experienced psychiatrist.A brief description of the sessions is as follows:Session 1: This session involved introducing the program to the participants, establishing relationships with them, providing a definition and explanation of thyroid disorders and its effect on sexual dysfunction, examining the causes of thyroid disorders, effective factors and history of the problem, examining the medical history of the clients and their physiological condition, examining the relationship between the couple’s interest in each other, the type of their marriage, and the type, frequency and quality of sexual relations between them, conducting sexual interviews, stating the logic, value and importance of treatment, stating the goals of counseling based on CBT, providing a brief explanation about the course and type of treatment, assigning homework.Session 2: This session was devoted to evaluation of dysfunctional sexual thoughts and beliefs in thyroid disorder. This included the following: Assessment of Illness-related thoughts, emotions, beliefs, behaviors and physical symptoms, evaluating dominant negative sexual attitudes, examining irrational sexual beliefs and explaining them from a scientific point of view, examining sexual preferences and desires of couples and how to express them to each other, reviewing sexual attitudes of women with thyroid disorders, examining the physical and emotional phases of couples during intercourse, assigning homework.Session 3: This session addressed the cognitive reconstruction and transformation of negative attitudes towards sexual issues in thyroid disorder. This included the following: review of the second session, cognitive reconstruction for psychological adjustment to chronic health problems, cognitive reconstruction for increase the ability to deal with annoying thoughts and negative attitudes related to the disease, cognitive reconstruction for increase the patient’s ability to improve mood, cognitive reconstruction of sexually dysfunctional thoughts in patients with thyroid disorders, homework assignment.Session 4: This session provided sexual information and knowledge in relation to thyroid disorder. This included the following: introducing the factors contributing to proper sexual dysfunction, getting familiar with sexual organs, physiological functions and their hormones, offering training on sex sensitive points, the benefits of sexual intercourse from a psychological and physical point of view, the role of women in sexual relations, communication skills, assigning homework.Session 5: This session dealt with training on non-sexual sensate focus. This included the following: reviewing the fourth session, training on body sensate focus, training on developing concentration and attention skills with respect to non-genital organs, examining verbal communication and how couples express their emotions to each other, teaching emotion expression, verbalization of emotional feelings, and sexual self-expression, enhancing intimacy between couples, assigning homework.Session 6: This session was concerned with training on sexual sensate focus. This included the following: reviewing the fifth session, providing more information about the genitals and sexually sensitive points, increasing self-awareness and sexual self-efficacy, offering training on concentration on sexual organs, attention to excitement and pleasure of the genitals, and sexual fantasies, assigning homework.Session 7: This session focused on teaching how to have sex in relation to an existing problem. This included the following: reviewing the fifth and sixth sessions, teaching different types of intercourse methods, teaching different types of intercourse methods tailored to the couple’s problem and related techniques, assigning step-by-step homework, G spot point maneuvering, teaching how to reach simultaneous orgasm in accordance with the couple’s sensitive points, assigning homework.Session 8: This session was dedicated to the assessment of the achievement of therapy goals. This included the following: reviewing the seventh session, evaluating various techniques used by couples, giving feedback on the effectiveness or ineffectiveness of therapy, resolving the existing problems, evaluating the positive results of the therapy program.In addition, participants were asked to practice the assignments presented in the therapy sessions for 30 min a day, 6 days a week, using the handouts provided.Because the control group received only standard medical treatment and the routine training provided in health centers, in order to observe ethical considerations and acknowledge their participation, they were given a manual along with a training CD at the end of the intervention.
PMC10204666
Data collection tools
In this study, data were collected using a demographic information form and Female Sexual Function Index (FSFI).The demographic information form included age, duration of illness, body mass index (BMI), level of education, and occupation.The Female Sexual Performance Index (FSFI) was developed by Rosen et al. in 2000 [In Rosen et al., the reliability of this questionnaire was evaluated, and the Cronbach’s alpha coefficient for all domains was 0.82 and above, and for the whole scale, it was 0.97 [
PMC10204666
Outcome assessment
Immediately and 4 weeks after completion of cognitive-behavioral therapy program, the demographic questionnaire and FSFI were completed once again by both case and control groups.
PMC10204666
Statistical analysis
The normal distribution of the data was measured using the Kolmogorov-Smirnov and Shapiro-Wilk tests. Data were analyzed using descriptive statistics (mean, standard deviation, frequency and percentage), independent t-test, chi-square test and repeated measures ANOVA test by SPSS statistical software version 23. P less than 0.05 was considered as statistically significant.
PMC10204666
Results
hypothyroidism, Pain
HYPOTHYROIDISM
In this study, 66 reproductive-aged women with hypothyroidism were recruited and divided into intervention (n = 33) and control (n = 33) groups. (Fig.  Flowchart of the progress through the phases of the trialBefore the treatment, the difference between the case and control groups in terms of the mean of Age (year), Body Mass index (Kg/m Comparison of demographic-obstetric characteristics of women with hypothyroidism in case and control groups*: Independent t-test, **: Chi-square testBased on the results this study, it was found that the mean scores of sexual function before, immediately after, and 4 weeks after completion of cognitive-behavioral therapy program were statistically significant in the CBT group (p < 0.05), but there was no significant difference between the mean scores of sexual function in the control group, before, immediately after, and 4 weeks after the start the intervention (p < 0.05).Also, the results showed that the difference between the case and control groups in terms of the mean total scores of sexual function and its dimensions (Desire, Arousal, Lubrication, Satisfaction, Orgasm and Pain) before the intervention was not significant (p > 0.05), but immediately and 4 after completion of intervention, this differences were statistically significant (p < 0.05) (Table  Comparison of mean and standard deviation of sexual function and its dimensions in case and control groups before and after cognitive-behavioral therapy#Post-treatment: Immediately after completion treatment; $Follow-up: 4 weeks after completion of treatment*: Independent t-test, **: Repeated measures analysis of variance; &Effect Size d Cohen Changes in total sexual function score before and after the treatment in case and control groups*Post-treatment: Immediately after completion treatment; **Follow-up: 4 weeks after completion of treatment The comparison of Mean of 6 independent domains of the Female Sexual Function Index (FSFI) in case and control groups*Post-treatment: Immediately after completion treatment; **Follow-up: 4 weeks after completion of treatment
PMC10204666
Discussion
thyroid disorders, illness behaviors, anxiety, obsessive compulsive disorder, vaginismus, Amiri, chronic diseases, pain, sexual dysfunction, psychiatric, chronic physical illness, hypothyroidism, sexual desire, diabetes
THYROID DISORDERS, DISORDER, CHRONIC ILLNESSES, VAGINISMUS, CHRONIC DISEASES, DISORDERS, MALE SEXUAL DYSFUNCTION, HYPOTHYROIDISM, DIABETES
The present study was carried out to evaluate the effect of CBT on sexual function in women with hypothyroidism. According to the findings, CBT improved the six dimensions of female sexual function including desire, arousal, lubrication, orgasm, satisfaction, and pain, as well as the total sexual function score in women with hypothyroidism immediately and 4 weeks after completion of cognitive-behavioral therapy program.According to Romero-Gómez et al. (2020), compared with controls, the prevalence of sexual dysfunction was higher in women with hypothyroidism despite levothyroxine treatment. Based on their results, hypothyroidism increased the risk of sexual dysfunction, with the most affected domains being desire, orgasm, and pain [Amiri et al. (2015) reported that in patients with hypothyroidism, the level of anxiety and stress is undesirable, which can be due to hypothyroidism. Therefore, they concluded that in addition to alternative treatment with levothyroxine, treatment of associated psychological problems is essential in these patients [Mestre-Bach et al. (2022) conducted a review study. They focused on “the psychotherapeutic approaches used in the treatment of female sexual dysfunction disorders” and reported cognitive-behavioral counseling as a successful treatment [Since at the time of writing this manuscript, we found no study on the application of cognitive-behavioral therapy aimed at the treatment of sexual dysfunction in reproductive-aged women with hypothyroidism, we tried to compare the results of the present study with those of studies examining the effect of cognitive-behavioral therapy in individuals with sexual dysfunction without underlying disorders or in patients with other chronic diseases.The results of Nezamnia et al. (2020) and Ahi et al. (2018) showed that cognitive-behavioral counseling can improve sexual desire in women and lead to increased sexual desire and sexual attraction in them [By the same token, Sabetnejad et al. (2016) found that the cognitive-behavioral counseling program together with fluoxetine significantly increases sexual performance in women with obsessive compulsive disorder [Ziaee et al. (2014) also reported the effect of cognitive-behavioral counseling on vaginal lubrication in women [Hamid et al. (2012) found that CBT led to increased sexual function in women with vaginismus [The hypothyroidism has been shown to be associated with an increased incidence of sexual dysfunction even when normalized with levothyroxine and thyroid stimulating hormone (TSH) [As mentioned earlier, due to the insufficient studies conducted on this topic, the effect of cognitive-behavioral therapy on improving sexual function and its mechanisms in chronic diseases such as thyroid disorders have not been studied thoroughly yet. Factors such as psychiatric disorders associated with chronic illnesses including health anxiety, coping problems, and difficulty in compliance with treatment, as well as problems with illness behaviors may play a role in the development of sexual dysfunction in patients with chronic diseases CBT has been proposed as a very effective and possibly cost-effective treatment for managing anxiety caused by health problems [Lukkahatai et al. (2019) also pointed to the role of cognitive-behavioral therapy in managing chronic diseases, controlling the symptoms, and improving the quality of life [Cognitive-behavioral therapy is used to treat psychiatric disorders not only in patients with chronic physical illness, but also in those who do not have a psychiatric disorder but have problems with illness-related beliefs, illness behaviors, or illness adaptation [Cognitive-behavioral therapy has been shown to be effective in improving sexual dysfunction in women with diabetes [Therefore, given the results of studies on the effects of chronic diseases on sexual dysfunction on the one hand and the effect of CBT on the improvement of these disorders on the other, and considering the results of this study, it can be argued that the use of this treatment along with standard treatments can play an important role in promoting sexual function in these patients.The most important strength of the present study was the novelty of its topic, and it was the first study to investigate the effectiveness of using cognitive-behavioral counseling along with pharmacotherapy to treat sexual dysfunction in women with hypothyroidism. Conducting the treatment sessions under the supervision of an experienced psychiatrist is another strength of this study.Nevertheless, a limitation that should be taken into account is that this study was conducted during the Covid-19 pandemic, which caused anxiety and stress among the participants for attending the sessions. This problem was minimized by reducing the number of people attending the sessions, providing a completely appropriate space for them, and observing hygienic protocols.
PMC10204666
Acknowledgements
This article was extracted from the master’s thesis of Azam Sheikh Miri, an M.Sc student of midwifery at Ahvaz Jundishapur University of Medical Sciences (Ref. ID: IR.AJUMS.REC.1398.387). This study was also registered in the Iranian registry for clinical trials (Ref. ID: IRCT20200706048030N1). The authors would like to express their gratitude to the Vice Chancellor for Research and Technology of Ahvaz Jundishapur University of Medical Sciences for supporting this project, as well as the officials and staff of Health Center No. 1, and the Comprehensive Medical Services Center No. 4 of Izeh, and all the participants of this research.
PMC10204666
Authors’ contribution
Authors’ contributions: AS: responsible for design, data collection and writing the manuscript in Persian. MI: responsible for design, data interpretation and writing the manuscript in English. HB: involved in design and interpretation of data. ML: responsible for data analysis and interpretation. All authors reviewed and approved the final manuscript.
PMC10204666
Funding
This article was extracted from a MSc. Thesis written in the School of Nursing and Midwifery, Ahvaz Jundishapur University of Medical Sciences (AJUMS), Ahvaz, Iran, and sponsored by the Deputy of Research of AJUMS, Ahvaz, Iran. This deputy has no role in design of the study, collection, analysis, and interpretation of the data and in writing the manuscript.
PMC10204666
Data Availability
The datasets generated and/or analyzed during the current research are not publicly available as individual privacy could be compromised but are available from the corresponding author on reasonable request.
PMC10204666
Declarations
PMC10204666
Ethics approval and consent to participate
This paper has been adapted from a MSc. thesis written by Miss Azam Sheikh Miri, recorded in Iranian clinical trial registration center with the code of IRCT20200706048030N1 and approved by Ethics Committee of Ahvaz University of Medical Sciences (Ref. No.: IR.AJUMS.REC.1398.387 ). All methods were performed in accordance with the relevant guidelines and regulations of the Declaration of Helsinki. We confirm that written informed consent was taken from all study participants before data collection.The ethics approval code is: Ref. ID: IR.AJUMS.REC.1398.387. IRCT registration number IRCT20200706048030N1, (01/09/2020)
PMC10204666
Consent for publication
Not applicable
PMC10204666
Competing interests
No conflict of interest has been declared by the authors.
PMC10204666
Abbreviations
Cognitive-behavioral therapyThyroid-stimulating hormoneSubclinical hypothyroidismFemale sexual function IndexBody mass index
PMC10204666
References
PMC10204666
Methods
CIN
SECONDARY, CIN
This was a prospective randomized controlled study including patients on chronic atorvastatin therapy. We randomly assigned the population to the Atorvastatin Reloading group (AR group), by reloading patients with 80 mg of atorvastatin one day before and three days after the coronary procedure, and the Non-Reloading group (NR group), including patients who received their usual dose without a reloading dose. The primary endpoints were the incidence of cystatin (Cys)-based CIN and Creatinine (Scr)-based CIN. The secondary endpoints consisted of the changes in renal biomarkers (Δ biomarkers) defined as the difference between the follow-up level and the baseline level.
PMC10166561
Results
CIN, type 2 diabetes
TYPE 2 DIABETES, CIN
Our population was assigned to the AR group (n = 56 patients) and NR group (n = 54 patients). The baseline characteristics of the 2 groups were similar. Serum creatinine (SCr)-based CIN occurred in 11.1% in the NR group, and in 8.9% in the AR group without any significant difference. Cys-based CIN occurred in 37% in the NR group and 26.8% in the AR group without any significant difference. The subgroup analysis showed that high dose reloading had significantly reduced the CYC-based CIN risk in patients with type 2 diabetes (43.5% vs 18.8%, RR = 0.43. CI 95% [0.18–0.99])). The comparison of “Δ Cystatin” and Δ eGFR between the AR and NR groups didn’t show any significant difference. However, cystatin C had significantly increased between baseline and at 24 hours in the NR group (0.96 vs 1.05, p = 0.001), but not in the AR group (0.94 vs 1.03, p = 0.206).
PMC10166561
Conclusions
CIN, diabetic type 2
CIN
Our study did not find a benefit of systematic atorvastatin reloading in patients on chronic atorvastatin therapy in preventing CIN. However, it suggested that this strategy could reduce the risk of CyC-based CIN in diabetic type 2 patients.
PMC10166561
Data Availability
All relevant data are within the manuscript and its
PMC10166561
Introduction
CIN
CONTRAST-INDUCED NEPHROPATHY, COMPLICATION, CIN
Contrast-induced nephropathy (CIN) is a common complication occurring in 5 to 11% of angiographic procedures [
PMC10166561
Methods
PMC10166561
Study population
cardiogenic shock, CM, acute coronary syndrome, fever
CARDIOGENIC SHOCK, LIVER DAMAGE, CARDIAC INSUFFICIENCY, INFECTIOUS DISEASE, ACUTE CORONARY SYNDROME, MALIGNANT TUMOR, ALLERGY TO CONTRAST MEDIA
This was an interventional prospective, randomized, single-blind, controlled trial, implemented in all consecutive patients (older than 18 years), undergoing coronary angiography or percutaneous coronary intervention in our department between June 2020 and September 2020 and who had already been receiving atorvastatin for at least one week, before admission.We didn’t include in the present study patients with the following criteria: patients admitted because of an acute coronary syndrome in whom a loading dose is mandatory according to guidelines, statin-naïve patients, patients who received a statin other than atorvastatin before the procedure, patients already receiving 80 mg atorvastatin, patients requiring dialysis and those with eGFR less than 15 ml/min/ 1.73 m2, patients who were exposed to a Contrast Medium (CM) within 7 days, patients with an allergy to contrast media, patients with cardiogenic shock or severe cardiac insufficiency (left ventricular ejection fraction LVEF <20%), patients with severe liver damage, malignant tumor, infectious disease, or fever, and those who refused to consent. We also excluded the patients who didn’t return to get control laboratory tests.The regional ethics committee (The Committee of Protection of the Persons in the South of the country: CPP South) approved the study and all participants signed the written informed consent.The protocol of the study was registered on the Pan-African Clinical Registry (PACTR). The registration number of the study is: PACTR202110707328144.
PMC10166561
Study protocol
CKD, dyspnea, nephrotoxic, CRF, CM
CRF
We randomly assigned all patients to either the Atorvastatin Reloading group (AR group) or the Non-Reloading group (NR group) according to a computer-generated random series of numbers. The randomization occurs one day before the coronary procedure. Patients in the AR group received oral atorvastatin 80 mg daily one day before and then 3 days after contrast media administration, followed by their habitual dose; patients assigned to the NR group received their habitual dose (atorvastatin 40 mg, 20 mg, 10 mg) without an additional reloading dose.In accordance with the ESC guidelines, we suspended the nephrotoxic drugs one day before the procedure (aldosterone antagonists, inflammatory inhibitors) in all patients. The renin-angiotensin inhibitors and metformin were withheld if patients showed a moderate CKD (defined by an eGFR <60 mL/min/1.73 m²) [All patients were treated with intravenous hydration with isotonic saline (0.9% sodium chloride) for 12 hours before and 12 hours after the procedure at the rate of 1 ml/Kg/H (0.5 ml/kg/H if LVEF <40% or if the patient suffered from dyspnea) and received the same nonionic dimeric iso-osmolar Contrast Media (CM) (Iopromide. ULTRAVIST 300 (300 mg d’Iode/mL). The nurses performed drug delivery and hydration. This designed study was single-blind. The physician who performed the coronary procedure was blinded to the patient’s group, but the patient was aware of his group.The nurses (3 females) collected demographics, clinical, and biological data for all patients: age, gender, body mass index (BMI), cardiovascular risk factors, co-morbidities, clinical presentation, the kind of procedure (coronary angiography or PCI), left ventricle systolic function, and current medication. No relationship was established prior to the study commencement. The interview was not repetad. The details of the procedure were also documented. All the data were collected in a CRF that was not returned to the participant. The participants didn’t provide feedback on the findings. Data saturation was not discussed.
PMC10166561
Laboratory parameters
BLOOD
Blood samples were collected to measure the baseline values of Serum Creatinin (SCr), Cystatin C (Cys), inflammatory factors (high sensitive C-reactive protein [hsCRP]), and pro-BNP on admission, and of course, before the loading dose administration. The post-procedural levels of Cys were measured 24 hours after the coronary procedure, the SCr, and the hsCRP at 72 hours. Previous studies had shown that the peak of cystatin C elevation occurred by the 24
PMC10166561
Study end-points and definitions
CIN, acute kidney injury
SECONDARY, CIN
The primary endpoints were the incidence of Cys-based CIN defined as an increase in serum CyC concentration by 10% above the baseline value 24 hours after contrast media administration [The secondary end-point was to detect any acute kidney injury by a significant rise in cystatin C level between baseline and 24 hours in the two groups (Δ cystatin).The changes in renal biomarkers (Δ biomarkers) are defined as the difference between the follow-up level and the baseline level. These changes were compared between the two groups (AR and NR groups).We assessed the risk of CIN before the procedure using the Mehran score [
PMC10166561
Statistical analysis
CIN
EVENT, CIN
Statistical analyses were carried out using SPSS software version 23 (SPSS Inc., Chicago. Illinois, the USA). We expressed categorical variables as percentages, and continuous variables as mean values (±standard deviation [SD]) when the distribution was normal or medians with semi-interquartile ranges (SIQR) when it was not normal. Normally distributed continuous variables were compared using the Student t-test (independent sample t-test for comparison between the 2 groups, paired sample t-test for self-comparison); non-normally distributed continuous variables were analyzed by non-parametric test (Mann-Whitney U test for independent series and Wilcoxon test for paired series). When the application conditions were validated, categorical data were analyzed using the Chi2 test of Pearson, otherwise Fisher exact test.Given the lack of similar studies in the literature, we carried out a pre-survey on 20 patients to determine the number of subjects needed. It was speculated that the incidence of CyC-based CIN was 36% in the NR group. We hypothesized the additional loading dose of Atorvastatin in the AR group could reduce the incidence of CyC-based CIN to 15%. Thus, the calculated sample size was at least 51 individuals for each group to get 80% power with a significance level of 0.05 (for the unilateral test). We have included an additional 10% of the workforce calculated taking into account the risk of loss of follow-up.The number needed to treat to prevent one event was calculated according to this formula: NNT = 1/ARR with ARR = Absolute Risk Reduction.
PMC10166561
Results
Four hundred forty-eight patients underwent coronary procedures during the study period. According to inclusion criteria, 120 patients were randomly assigned to the Atorvastatin Reload group (AR group, n = 60) and the Non-reloading group (NR group, n = 60) (
PMC10166561
Trial flowchart.
CKD, diabetes
CORONARY DISEASE, HYPERTENSION, DYSLIPIDEMIA, DIABETES
Our population was at high cardiovascular risk, 58.2% of patients were smokers, 60.9% had hypertension, 51.8% had diabetes, 81% had dyslipidemia, 7.3% had moderate CKD, and 34.5% had a history of coronary disease. Sixty-six percent of our patients had at least three cardiovascular risk factors. All patients had been receiving atorvastatin for more than one month before the coronary catheterization (58.2% received 40 mg of atorvastatin, 7.3% received 20 mg of atorvastatin, and 34.5% received 10 mg of atorvastatin).The baseline clinical characteristics and laboratory results are summarized in Tables
PMC10166561
Baseline clinical characteristics in our population.
CM
ACE: angiotensin-converting enzyme, CM: Contrast Media, Cv: cardiovascular, LVEF: Left Ventricle Ejection Fraction, NYHA: New York heart association, PCI: Percutaneous Coronary Intervention, SD: Standard deviation, SIQR: semi-interquartile range, UD: urine dipstick
PMC10166561
Baseline clinical laboratory tests in our population.
CIN
BRAIN, CIN
Data are expressed as median (SIQR: semi-interquartile range).ALAT: alanine aminotransferase ASAT: aspartate aminotransferase, CK: creatine kinase levels, LDH: Lactate dehydrogenase, LDL: Low-density cholesterol, eGFR: estimated glomerular filtration rate;, hsCRP: high-sensitivity C-reactive protein; intervention, ProBNP: Pro Brain natriuretic peptideThe primary end-point of SCr-based CIN occurred in 11 patients (10%). There was no statistical difference in Scr-based CIN incidence between the AR group and the NR group (11.1% versus 8.9%, p = 0.7). The overall incidence of CyC-based CIN was higher than Scr-based CIN and it was calculated to be 31.8% (35/110) of the patients. This incidence was 37% in the NR group and 26.8% in the AR group without any statistical difference between the two groups (p = 0.24) (
PMC10166561
Comparison of contrast induced nephropathy between groups.
CIN, nephropathy
CONTRAST-INDUCED NEPHROPATHY, RENAL FAILURE, CIN, NEPHROPATHY, HEART FAILURE, TYPE 2 DIABETES
AR group: patients who received a reloading dose of 80 mg atorvastatin, Cys-CIN: Contrast-induced nephropathy based on cystatin C levels, NR group: patients who did not receive a reloading dose, Scr-CIN: contrast induced nephropathy based on Serum creatinine levels.The analysis of subgroups who are known as a high-risk CIN population (patients with renal failure, patients aged > 70 years, type 2 diabetes, patients with Mehran score > 10, patients with heart failure, patients on ACE/ARBs) showed a benefit of additional atorvastatin reloading only in the type 2 diabetes group. The CyC-based CIN in patients with type 2 diabetes was significantly lower in patients who received a reload dose of atorvastatin than those didn’t receive a reload dose of statin (18.8% vs 43.5%,p = 0.046, RR = 0.43, Confidence Interval 95% [0.18–0.99]) (
PMC10166561
Comparison of contrast induced nephropathy between the two groups in diabetes 2 patients (n = 55).
CIN, diabetic, nephropathy
CONTRAST-INDUCED NEPHROPATHY, NEPHROPATHY, CIN
AR group: patients who received a reloading dose of 80 mg atorvastatin, Cys-CIN: Contrast-induced nephropathy based on cystatin C levels, NR group: patients who did not receive a reloading dose, Scr-CIN: contrast induced nephropathy based on Serum creatinine levels.Paradoxically, SCr-based CIN was similar between the AR group and the NR group even in type 2 diabetic people.When comparing changes of renal biomarkers (Δ cystatin, Δcreatinine and Δ Cys-eGFR) between the AR group and the NR group, there were no significant differences (
PMC10166561
Comparison of changes in renal biomarkers between the AR and the NR groups.
BRAIN
All Variables are expressed by median (semi-interquartile range).Δ: difference between the follow-up level and the baseline levelAR group: Atorvastatin reloading group, Cys: cystatin C; hsCRP, C-reactive protein; Cys-GFR, glomerular filtration calculated using cystatin level; NR group: Non-reloading group, SIQR: semi-interquartile range. ProBNP: Pro Brain natriuretic peptide.
PMC10166561
Discussion
CKD, toxicity, medullary hypoxia, nephrotoxic, diabetic type 2, CM, acute coronary syndrome, diabetic, CI-AKI, CIN, diabetes
INFLAMMATORY RESPONSES, CONTRAST-INDUCED ACUTE KIDNEY INJURY, COMPLICATION, CIN, ACUTE CORONARY SYNDROME, OXIDATIVE STRESS, DIABETES
Contrast-induced acute kidney injury (CI-AKI) is a common complication of CM intravascular injection; the physiopathology is complex and not well-understood. Our randomized trial aimed to assess the impact of a reloading dose with 80 mg of atorvastatin on CIN incidence in patients who underwent coronary invasive procedures and who were pre-treated with atorvastatin. The incidence of Scr-based CIN was 10% and the incidence of CYs-based CIN was 31.8% in our trial. In previous studies, the incidence of CYs-CIN ranged between 11 and 28% [The mechanisms of CIN are not well-understood. The most recognized mechanisms are renal vasoconstriction, medullary hypoxia, direct tubular cell toxicity of CM, inflammatory mechanisms, and oxidative stress. All these factors lead to epithelial and endothelial cell apoptosis and GFR reduction [The beneficial impact of statins in CIN prevention has been largely demonstrated [Our trial suggested that reloading with high-dose atorvastatin reduces the risk of CIN in diabetic type 2 patients. This beneficial effect could be explained by a reduction in inflammatory reactions after contrast injection, as it was assessed by the significant increase of the hs-CRP level in the NR group and not in the AR group.Prophylactic treatment with high-dose atorvastatin reduced the incidence of both SCr- and CyC-based CIN in patients with ACS following PCI, which might be attributed to its properties of reducing oxidative stress and inhibiting inflammatory responses.Reloading with atorvastatin was not superior to maintaining the habitual dose in non-diabetic patients and the overall population. This finding could be explained by the population included in the study, where we already used many means of CIN prevention (chronic statin therapy, rehydration, withdrawal of nephrotoxic drugs, low osmolar contrast products), and it could be difficult to show a benefit from an additional strategy. However, the control group included patients who were already on chronic statins. We recall that in the previous statin studies, the control group included statin-naïve patients.A recent meta-analysis, including seven RCTs of 4256 participants proved that the risk of developing CIN in patients with CKD pre-treated with statins was significantly lower than that in patients pre-treated with placebo (RR = 0.57. 95%CI = 0.43–0.76. p<0.001); in the subgroup analysis, statin pre-treatment could decrease the risk of CIN in CKD patients with diabetes (RR = 0.54. 95% CI = 0.39–0.76. p<0.001), but not in CKD patients without DM (RR = 0.84. 95% CI = 0.44–1.60. p = 0.606) [Paradoxically, Naikuan et al who compared the efficacy of high-dose atorvastatin (40 mg) to conventional-dose atorvastatin (10 mg) on the prevention of CIN in patients with acute coronary syndrome undergoing percutaneous intervention didn’t find a beneficial impact in diabetic groups and they attributed this finding to the low proportion of high-risk patients or lower dose of atorvastatin compared to the studies mentioned above [
PMC10166561
Study limitations
CIN
CIN
The present study had some limitations. Firstly, it was a single-center, single-blinded study. Only the patients were aware of the inclusion group because we didn’t use a placebo for patients in the NR group. Nevertheless, the two doctors who performed the coronary intervention and ensured the follow-up were blinded to the patient’s group. This limitation seems not to have impacted the results since the data of the study did not depend on the psychological state of the patient. Secondly, given that the patients were followed for only 72 hours after the procedure to diagnose CIN, we didn’t evaluate the morbidity associated with CIN.
PMC10166561
Conclusions
CI-AKI, CIN, diabetic
DIABETES TYPE 2, CIN
Our study was the first randomized trial in the literature that assessed the beneficial effect of 80 mg atorvastatin reloading on CI-AKI in patients pre-treated with this drug at a lower dose. Our population was at high risk with a high prevalence of cardiovascular factors. We did not find a beneficial effect on the overall population. However, the subgroup analysis showed that this intervention reduces the risk of Cys-based CIN in patients with diabetes type 2. Thus, a short-term reloading regimen of atorvastatin could be advised before coronary catheterization in diabetic patients.
PMC10166561
Supporting information
PMC10166561
CONSORT checklist.
(DOC)Click here for additional data file.
PMC10166561
Ethic agreement.
(PDF)Click here for additional data file.
PMC10166561
Study design.
(DOCX)Click here for additional data file.
PMC10166561
Pan-african-trial registry- registration.
(PDF)Click here for additional data file.
PMC10166561
Protocol of the study.
(DOCX)Click here for additional data file.
PMC10166561
COREQ (COnsolidated criteria for REporting Qualitative research) checklist.
(PDF)Click here for additional data file.(XLSX)Click here for additional data file.
PMC10166561
References
PMC10166561
Subject terms
Dried blood spot (DBS) sample collection has been suggested as a less invasive, cheaper and more convenient alternative to venepuncture, which requires trained personnel, making it a potentially viable approach for self-collection of blood on a large scale. We examine whether participants in a longitudinal survey were willing to provide a DBS sample in different interview settings, and how resulting cardiovascular risk biomarkers compared with those from venous blood to calculate clinical risk. Participants of the
PMC10415328
Introduction
DBS and venous blood sample, death, Cardiovascular disease
DISEASE, CARDIOVASCULAR DISEASE, CARDIOVASCULAR DISEASE
Cardiovascular disease is the leading cause of death worldwide. In the UK, cardiovascular disease is patterned by several social and environment factorsStandard protocols for blood sample collection require face-to-face contact. Most commonly, collection of bio-specimens for research takes place in a clinic and/or the participant’s home by a trained phlebotomist or nurse. Research clinics, typically a medical or research facility or ‘mobile clinic’, provide expert medical personnel, phlebotomists, and specialised equipment to ensure the appropriate handling of samplesThe resource challenges of the above approaches can be addressed by dried blood spot (DBS) sampling, which is a low resource-demanding alternative to venous blood draws, and as less invasive, may be more acceptable to participants. DBS samples are small volumes of capillary blood, obtained by fingerprick and blotting of the blood onto filter paper. This method, which has been used in new born screening programmes, reduces personnel and shipping costs, and is an accepted means of collecting blood samples in a research settingA number of social studies such as National Social Life, Health, and Aging projectFor the successful use of DBS in population surveys, it needs to be demonstrated that the characteristics of participants that complete a DBS collection are not systematically different compared to those that provide venous blood. Further, to enable population level estimates of disease, it is necessary to determine whether analyte concentrations measured in DBS and venous blood samples are equivalent. To address these issues, we included DBS and venous blood sample collection in a randomised study of the general population. The aims of this study were (a) to describe the demographic characteristics of participants that took part in the survey, consented to give venous and/or DBS samples, and who provided good quality DBS samples; (b) to estimate serum-equivalent DBS values and compare results to venous samples, investigating how blood sample characteristics affects the agreement between the two measures; c) to investigate if serum-equivalent DBS measures are suitable to assess clinical risk.
PMC10415328
Methods
This paper uses data collected in the
PMC10415328
Sample processing
RECRUITMENT
In IP12Flowchart showing IP12 recruitment and consent to provide blood samples.After reception at MRC Epidemiology Unit, venous blood samples for glycated haemoglobin were refrigerated until analysis. The remaining venous blood samples were centrifuged, and aliquots of plasma and serum were stored at − 70 °C until analysis. DBS samples were received at the University of Essex, stored at room temperature, batched and sent to MRC Epidemiology Unit where they were later frozen at − 70 °C until analysis. DBS samples were stored in small plastic bags with a sachet of desiccant. The DBS samples were graded by visual inspection and given two scores: (1) number of useable spots (0–5 useable spots or missing if no spots) and (2) if applicable, a quality code to describe the spots (operationalised as either: good quality with no issues, not dried, other issue, or not dried and additional issue). The latter is based on commonly used DBS grading charts
PMC10415328
Analytes
Total cholesterol, triglycerides and CRP from serum and DBS and glycated haemoglobin from whole blood or serum and DBS were measured using a Siemens Dimension Xpand clinical chemistry analyser (Siemens Healthcare Ltd, Camberley, Surrey, UK). Method details including extraction from DBS, as well as reagents, control quality materials and QC information can be found in Supplementary Materials Except for CRP, the use of third-party reagents (Randox Laboratories, County Antrim, UK) allowed assays to be programmed manually on the analyser and enabled the parameters recommended for serum assays to be adapted for the higher sensitivity required for DBS analysis. This approach kept the serum and DBS assays as closely aligned as possible to reduce bias between methods. CRP was assayed using the Siemens Dimension Xpand CardioPhase® high sensitivity assay. Serum CRP was measured according to the manufacturer’s instructions. To use the same CRP method for DBS, the assay was calibrated using a 50-fold dilution in PBS of the manufacturer’s recommended kit calibrator (CCRP calibrator). This dilution was chosen to be equivalent to the CRP in the DBS eluent. In all other aspects the assay was run using the manufacturer’s protocol for serum CRP and provided equivalent results for the sample types (Supplementary Materials Measurements of triglycerides, HbA1c and CRP did not meet the assumption of normality assessed using Shapiro–Wilk tests. To overcome this, triglyceride and CRP data were log transformed and inverse measures for HbA1c were used for equivalency. (Supplementary Materials
PMC10415328
Covariates
For both venous and DBS results, the time a sample was kept at room temperature was calculated as the time between sample collection by the nurse/participant and receipt at MRC Epidemiology Unit. All venous blood samples were processed before COVID-19 related laboratory closure. A variable was included to describe whether DBS samples were measured before or after the COVID-19-related lab closure. Other indicators of the quality of the DBS sample considered were the visual inspection score described above and the number of blood spots on the DBS card.Responses to questionnaires were used to record age, sex, highest level of education (obtaining a degree or higher
PMC10415328
Statistics
HbA1c diabetes, diabetes
REGRESSION, DIABETES, CVD
Descriptive statistics were used to compare response rates to the overall survey, consent rates for providing each type of blood sample and the provision of ‘good’ quality DBS samples by mode of interview. The population characteristics of participants who gave consent to give a venous blood sample, consent to a DBS blood sample, and provided a good DBS sample, by actual mode of interview, were compared using the Wilcoxon rank sum test for continuous variables and Pearson's Chi-squared test for categorical variables.To calculate venous equivalent-DBS values, for those participants with both samples, venous results were regressed on DBS raw sample values using Deming regression. This was carried out using the mcr R packageTo investigate how closely the raw DBS measures match those taken from venous blood or serum, where both measures were taken from the same participant, simple linear regression was used to compare venous or serum values with—venous-equivalent DBS values (Supplementary Materials Bland–Altman plots (Supplementary Material DBS and venous sample characteristics were investigated to understand if these impacted the agreement of raw DBS measures to venous-equivalence; analysis of variance was used to measure differences between a base model that included only the DBS values regressed on venous values, against another model where for each indicator of blood sample quality an interaction term between DBS and the covariate in question was included (Supplementary Material Cut-offs were used to estimate CVD risk in the venous-equivalent DBS measures; for HbA1c diabetes risk was defined as greater than 6.5%, high cholesterol at a threshold of 5 mmol/l, and high CRP at 10 mg/l. Pearson's Chi-squared tests were used to compare the proportion of participants’ with diagnosed diabetes and participants’ analyte levels that were above clinical cut-offs between the self-collected DBS samples and venous bloods collected by nurses. These analyses were carried out unweighted and weighted to adjust for the complex sample design and likelihood of being included in the Innovation Panel
PMC10415328
Ethics approval
The University of Essex Ethics Committee has approved all data collection on
PMC10415328
Results
Following contact, a number of participants failed to participate in the study. Reasons for failure to participate are shown in Supplementary Material
PMC10415328
Characteristics of participants who gave a full interview, consented to venous or DBS samples and provided a good DBS sample by mode of interview
In actual or realised mode, consent rates for biological sample collection were higher in the nurse mode (74%) than in those invited for self-collection (35%). Participants reported they were likely to take part again (likelihood of participating again score from 1 to 10: 8.8 ± 1.7) irrespective of whether they were seen by a nurse (8.8 ± 1.8) or not (8.9 ± 1.6).With the exception of age, there were no differences in the characteristics of those who consented to a DBS sample by nurse or self-collection (Table Participant characteristics of those who gave a full interview, consented to blood sample, and provided a good DBS sample by mode of interview/DBS sample collection.*
PMC10415328
Characteristics of DBS and venous samples by mode of sample collection
A higher proportion of nurse collected DBS samples were rated good quality compared with self-collected DBS, 80% vs. 47% (DBS and venous characteristics by final mode of interview limited to those whose DBS samples was analysed.
PMC10415328
DBS to venous measurement and equivalency
REGRESSION
In the venous and DBS samples where both samples yielded a measurement, for total cholesterol, CRP, triglycerides and HbA1c, there was a significant relationship between venous and DBS measures (For total cholesterol, CRP, triglycerides and HbA1c the following DBS-to-venous (serum or whole blood) equivalency equations were obtained by regressing serum or whole blood values on raw DBS values using Deming regression.The mean and standard deviation for venous and venous-equivalent DBS values for each analyte, by mode of sample collection, are shown in Table Total cholesterol, C-reactive protein, triglycerides, and glycated haemoglobin values for venous and serum-equivalent DBS data.
PMC10415328
Agreement between venous and DBS measures
Bland–Altman plots were used to assess agreement between venous-equivalent DBS compared to venous measures (Supplementary Materials
PMC10415328